SACUBITRIL + VALSARTAN (ENTRESTO®)















PARADIGM-HF study - Valsartan-Sacubitril vs Enalapril in Heart Failure with Reduced Ejection Fraction, NEJM (2014) [PubMed abstract]
  • The PARADIGM-HF study enrolled 8442 patients with NYHA class II - IV heart failure and an ejection fraction ≤ 40%
Main inclusion criteria
  • NYHA class II - IV heart failure
  • Ejection fraction ≤ 40%
  • BNP level ≥ 150 pg/ml or, if they had been hospitalized for heart failure within the previous 12 months, a BNP ≥ 100 pg/ml
Main exclusion criteria
  • SBP < 95 mmHg
  • CrCl < 30 ml/min
  • Potassium > 5.4 mmol/L
  • History of angioedema or unacceptable side effect with ACE or ARB
Baseline characteristics
  • Average age 64 years
  • Average SBP - 122 mmHg
  • Average ejection fraction - 29.5%
  • Median BNP - 253 pg/ml
  • NYHA class: I - 4.6% | II - 70% | III - 24% | IV - 0.7%
  • Concomitant meds: Beta blocker - 93% | Aldosterone antagonist - 55% | Diuretic - 80%
Randomized treatment groups
  • Group 1 (4187 patients) - Sacubitril 97 mg/Valsartan 103 mg mg twice a day
  • Group 2 (4212 patients) - Enalapril 10 mg twice a day
  • Before randomization, the trial had two run-in periods where patients who could not tolerate enalapril followed by Entresto were excluded. Most common reasons for exclusion were renal dysfunction, hypotension, and hyperkalemia.
Primary outcome: Composite of death from cardiovascular causes or a first hospitalization for heart failure
Results

Duration: After a median follow-up of 27 months, the trial was stopped early because of clear superiority of Entresto
Outcome Valsartan-Sacubitril Enalapril Comparisons
Primary outcome 21.8% 26.5% HR 0.80, 95%CI [0.73 – 0.87], p<0.001
Death from cardiovascular causes 13.3% 16.5% HR 0.80, 95%CI [0.71 – 0.89], p<0.001
First hospitalization for heart failure 12.8% 15.6% HR 0.79, 95%CI [0.71 – 0.89], p<0.001
Overall mortality 17% 19.8% HR 0.84, 95%CI [0.76 – 0.93], p<0.001
Hypotension 14% 9.2% p<0.001
Serum creatinine ≥ 2.5 mg/dl 3.3% 4.5% p=0.007
Potassium > 5.5 mmol/L 16.1% 17.3% p=0.15
Cough 11.3% 14.3% p<0.001
Angioedema 19 events 10 events N/A
  • At 8 months, the average SBP was 3.2 mmHg lower in the Entresto group than in the enalapril group (p<0.001)

Findings: Entresto was superior to enalapril in reducing the risks of death and of hospitalization for heart failure






PARAGON-HF Trial - Sacubitril-Valsartan vs Valsartan in Heart Failure with Preserved Ejection Fraction, NEJM (2019) [PubMed abstract]
  • The PARAGON-HF trial enrolled 4822 patients with NYHA class II - IV heart failure and an ejection fraction ≥ 45%
Main inclusion criteria
  • Age ≥ 50 years
  • NYHA class II - IV heart failure
  • Ejection fraction ≥ 45%
  • Elevated NT-proBNP
  • Structural heart disease (LA enlargement or LVH)
  • Current treatment with diuretic
Main exclusion criteria
  • Any prior ECHO with EF < 40%
  • ACS within 3 months
  • Current decompensated CHF
  • History of angioedema
  • Uncontrolled hypertension
Baseline characteristics
  • Average age 73 years
  • Average EF - 58%
  • Atrial fibrillation/flutter - 32%
  • History of MI - 22%
  • NYHA class: I - 2.8% | II - 77% | III - 20% | IV - 0.4%
Randomized treatment groups
  • Group 1 (2407 patients): Sacubitril-Valsartan 97/103 mg twice daily
  • Group 2 (2389 patients): Valsartan 160 mg twice daily
  • The trial had a run-in phase where patients received valsartan at half the target dose, followed by sacubitril– valsartan at half the target dose. Participants who had no unacceptable side effects in both run-in phases and whose laboratory values remained within prespecified safety criteria underwent randomization
  • Renin–angiotensin system inhibitors other than mineralocorticoid-receptor antagonists were discontinued before the run-in period, but all other background medications were continued
  • Study drugs were adjusted down if side effects occurred
Primary outcome: Composite of total (first and recurrent) hospitalizations for heart failure and death from cardiovascular causes
Results

Duration: Median of 35 months
Outcome Sacubitril-Valsartan Valsartan Comparisons
Primary outcome (%/year) 12.8% 14.6% RR 0.87, 95%CI [0.75 - 1.01], p=0.06
Hospitalization for heart failure 690 events 797 events RR 0.85, 95%CI [0.72 – 1.00]
Death from CVD 8.5% 8.9% HR 0.95, 95%CI [0.79 – 1.16]
Overall mortality 14.2% 14.6% HR 0.97, 95%CI [0.84 – 1.13]
Hypotension (SBP < 100) 15.8% 10.8% p<0.001
Serum creatinine ≥ 2.0 mg/dl 10.8% 13.7% p=0.002
Hyperkalemia > 5.5 mEq/L 13.2% 15.3% p=0.048
Angioedema 14 cases 4 cases N/A
Achieved target dose at end of trial 82% 85.1% N/A

Findings: Sacubitril–valsartan did not result in a significantly lower rate of total hospitalizations for heart failure and death from cardiovascular causes among patients with heart failure and an ejection fraction of 45% or higher






















  • ✝ Use of the Oral Suspension recommended in these patients. Recommended mg/kg doses are of the combined amount of both sacubitril and valsartan
  • ‡ Doses of 72/78 mg can be achieved using three 24/26 mg tablets
Titration Step Dose (twice daily)
Starting Second Final
< 88 lbs (40 kg)✝ 1.6 mg/kg 2.3 mg/kg 3.1 mg/kg
88 lbs (40 kg) to 109 lbs (50 kg) 24/26 mg 49/51 mg 72/78 mg‡
≥ 110 lbs (50 kg) 49/51 mg 72/78 mg‡ 97/103 mg